Title

Author

Degree

Doctor of Philosophy

Program

Biomedical Engineering

Supervisor

Dr. Wankei Wan

Abstract

Poly(vinyl alcohol) (PVA) was selected and evaluated as a controlled drug delivery matrix for Serp-1, a potential new therapeutic with anti-inflammatory properties for control of restenosis. PVA hydrogels, containing a high water content, can be formed by physical crosslinking via a process involving freezing and thawing the material in multiple cycles. PVA, being a well known biomaterial, is suited for biomedical applications and the high water content and hydrophilicity provides a friendly environment for the delivery of large protein based drugs. Using bovine serum albumin (BSA) as a model protein, the controlled release properties of PVA were investigated. Release profiles demonstrated diffusion controlled release and adjusting the number of freeze-thaw cycles resulted in a change in release rate. It was also determined that fabricating a reservoir-type system by adding an additional layer of protein-free PVA as an outer barrier provides a method of changing the release kinetics. From a one-layer matrix-type PVA/BSA system the release kinetics follow diffusion controlled release, while from a two-layer reservoir-type system the release kinetics are zero-order. The thickness of the outer barrier controlled the rate of BSA release. Using BSA as a model protein again, its release from PVA hydrogel into phosphate buffered saline (PBS) solutions of varying ionic strength was explored. The amount of BSA released was shown to be influenced by the ionic strength of PBS used as the release medium. Increasing the ionic strength of the release medium caused a reduction in mesh space of the hydrogel and increase in apparent PVA concentration, leading to a reduction in BSA release. These results are important to consider for applications in the physiological environment where salts are unavoidable.

The release of Serp-1 from PVA hydrogel was systematically investigated by considering the effect of the PVA processing parameters. A decrease in release rate was observed when the number of freeze-thaw cycles was increased, the PVA solution concentration was increased, or the freezing and thawing rates were decreased. By manipulating the different processing parameters studied, the diffusive properties of Serp-1 from PVA hydrogel could be controlled over a 30-fold range. In contrast to the PVA/BSA system where virtually all the protein is released, the amount of Serp-1 released from an equivalent system was found to be only approximately 50 % with the remaining protein trapped in the PVA matrix. This is likely due to a combination of factors including the possible stronger interaction of Serp-1 and PVA, as well as shrinkage of the hydrogel structure.

A therapeutic level of Serp-1 release was achieved by increasing the initial protein loading and with only two freeze-thaw cycles the release was extended over a period of approximately 100 hours. A promising PVA/Serp-1 controlled drug delivery system with tunable properties has been demonstrated. The use of such a controlled release system would offer an improvement over the current Serp-1 delivery method of infusion by gradually releasing Serp-1 over time at the local site of arterial injury. The system can be tuned to adjust the release rate of Serp-1 one by selecting the appropriate combination of processing conditions. The release kinetics can also be adjusted by selecting a one-layer matrix-type system or two-layer reservoir-type system. Therefore, there are many options to tune the PVA/Serp-1 system to meet therapeutic requirements once they are known following clinical trials of the new therapeutic agent.